The broad objective of this research is to identify central neurochemical changes that occur during stress and to determine if these changes aid in the development of adaptation and resistance to stress. In previous research on this project we have found that chronic footshock stress in rats leads to a reduction in the sensitivity of brain norepinephrine (NE) receptors, and that this change occurs at a time when animals show resistance to the deleterious effects of the stress. We have hypothesized that subsensitivity to NE is an adaptive mechanism that aids in the development of resistance to stress. The first aim of the proposed research is to obtain basic information on the mechanism of stress-induced subsensitivity which will facilitate the testing of this hypothesis. This will be accomplished (a) by determing the minimum amount of stress necessary to induce subsensitivity, (b) by studying the physiological events that lead to this change, and (c) by defining the molecular basis of this phenomenon. Data obtained from these studies will be used to develop methods to experimentally manipulate subsensitivity in order to test its role in adaptation. The second aim of the research is to test two predictions based on the above hypothesis. The first prediction states that subsensitivity of NE should occur after a variety of stressors other than footshock which also lead to resistance. This will be tested by examining the ability of chronic restraint, forced running and drum stress to elicit subsensitivity to NE in the rat brain. The second prediction states that non-stressful procedures which induce subsensitivity should enhance resistance to subsequent stress. This will be tested by determining if chronic pretreatment with antidepressant drugs, agents which are known to induce central subsensitivity to NE, leads to a reduced vulnerability to subsequent stress.